Primary biliary cirrhosis (PBC) is a progressive liver disease believed to be of autoimmune nature. Its etiology is unknown. It is characterized by progressive intrahepatic cholestasis as a result of ongoing non-suppurative destructive cholangitis that affects small intrahepatic bile ducts. It affects approximate 1 in 2,000 women above the age of 50 and it is one of the 3 or 4 major reasons for liver transplantation in the US. Several trials have been conducted to study the effect of immunosuppressants in PBC including methotrexate (MTX). A randomized trial comparing the effects of 7.5 vs 15 mg per week of oral MTX was started in 1991 and therapy was be completed in 1998. 28 patients were randomized to receive one of the two doses and stratified according to the presence or absence of symptoms. Therapy led to decreases in serum alkaline phosphatase and aminotransferase levels and falls of IgM levels to normal. Symptoms improved in 43 per cent of patients and liver histology in 46 per cent. The higher dose was associated with greater improvements in liver histology but the lower dose was effective in a similar percentage of patients. Prolonged therapy was able to maintain improvements in the percentage of patients who had a clinical or histological improvement in disease. These results indicate that prolonged therapy with adjusted doses of MTX may be effective in ameliorating symptoms and liver pathology in PBC. At present all patients are being followed and undergo reassessment three years after stopping methotrexate to assess the durability of clinical, biochemical and histological responses.